Synthesis of zearalanes II and related compounds and intermediates useful in the syntheses thereof

ABSTRACT

This invention provides a new synthesis for norzearalane II and related compounds which related compounds and norzearalane II are represented by the formula   where X is an integer having a value from 1 to 13 inclusive. The anabolic agent norzearalane II, in which X 9 in the foregoing formula, is prepared by a total chemical synthesis involving the reaction of 10-undecenal with malonic acid to produce trans-2,12-tridecadienoic acid; treating the acid so formed with diazomethane to yield methyl trans-2,12tridecadienoate; reacting the methyl ester with ethyl acetoacetate and sodium ethoxide to form the sodium salt of ethyl 6-(9-decenyl)- Beta -dihydroresorcylate; brominating the dihydroresorcylate to prepare ethyl 3-bromo-6-(9-decenyl)- Beta dihydroresorcylate; de-hydrobrominating the foregoing bromo derivative to give ethyl 6-(9-decenyl)- Beta -resorcylate; reacting the resorcylate ester with benzyl chloride to produce ethyl 6-(9-decenyl)- Beta -resorcylate dibenzyl ether; subjecting the benzylated ester to the action of diborane, water and hydrogen peroxide to form ethyl 2,4-bis(benzyloxy)-6-(10hydroxydecyl)-benzoate; treating the foregoing benzoate with sodium ethoxide to prepare norzearalane II dibenzyl ether, and also to prepare as a by-product the dimeric dilactone of 2,4bis(benzyloxy)-6-(10-hydroxydecyl)-benzoic acid; hydrogenating norzearalane II dibenzyl ether to form norzearalane II.

United States Pate Urry et al.

[ 51 Sept. 2, 1975 [75] Inventors: Wilbert H. Urry, Chicago, 111.; Guy Towns Mullenbach, Berkeley, Calif.

[73] Assignee: Commercial Solvents Corporation,

Terre Haute, Ind.

[22] Filed: Feb. 26, 1974 [21] Appl. No.: 445,860

Related US. Application Data [62] Division of Ser. No. 247,282, April 25, 1972, Patv [52] US. CL... 260/3431 F; 424/279; 260/343.2 R;

260/3433 [51] Int. Cl C07d 9/00 [58] Field of Search 260/3432 F, 343.2 R, 343.3

[56] References Cited UNITED STATES PATENTS 3,196,019 7/1965 Andrews ct a1 260/3431 Primary Examiner.lohn M. Ford Attorney, Agent, or Firm-Morton, Bernard, Brown, Roberts & Sutherland [57] ABSTRACT This invention provides a new synthesis for norzeara lane 11 and related compounds which related compounds and norzearalane 11 are represented by the formula HO (C 2) where X is an integer having a value from 1 to 13 inelusive,

The anabolic agent norzearalane II, in which X 9 in the foregoing formula, is prepared by a total chemical synthesis involving the reaction of lO-undecenal with malonic acid to produce trans-2,1Z-tridecadienoic acid; treating the acid so formed with diazomethane to yield methyl trans-2,1Z-tridecadienoate; reacting the methyl ester with ethyl acetoacetate and sodium ethoxide to form the sodium salt of ethyl 6-(9-decenyl)-B-dihydroresorcylate; brominating the dihydroresorcylate to prepare ethyl 3-bromo-6-( 9-decenyl )-B-dihydroresorcylate; de-hydrobrominating the foregoing bromo derivative to give ethyl 6-(9-decenyl)-B-resorcylate; reacting the resorcylate ester with benzyl chloride to produce ethyl 6-(9-deceny1)-,8-resorcylate dibenzyl ether; subjecting the benzylated ester to the action of diborane, water and hydrogen peroxide to form ethyl 2,4-bis( benzyloxy)-6-( 10-hydroxydecyl)-benzoate; treating the foregoing benzoate with sodium ethoxide to prepare norzearalane II dibenzyl ether, and also to prepare as a byproduct the dimeric dilactone of 2,4-bis(benzyloxy)-6-( lO-hydroxydecyl)-benzoic acid; hydrogenating norzearalane II dibenzyl ether to form norzearalane II.

14 Claims, N0 Drawings SYNTHESIS OF ZEARALANES II AND RELATED COMPOUNDS AND INTERMEDIATES USEFUL IN THE SYNTHESES THEREOF This is a division of application Ser. No. 247,282, filed Apr. 25, 1972, now US. Pat. No. 3,836,544.

In general, a homologue of norzearalane II and/or of the corresponding dimeric dilactone is prepared by substituting the lO-undecenal in the foregoing sequence of reactions an unsaturated aldehyde having the formula:

where X is an integer which may have the value 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11,12 or 13.

Specifically zearalane II (where X is prepared starting with l ldodecenal and the dimeric dilactone from 6-( S-hydroxypentyl)-B-resorcylic acid dibenzyl ether is prepared when the starting aldehyde is 5- hexenal (where X 4).

The invention also covers physiologically active compounds related to the zearalanes II and known as dimeric dilactones having the formula,

2 (cnzk R0 (CHZIX X is an integer which may have the value I, 2, 3, 4, 5, 6, 7, 8, 9, 10, I1, 12 or 13, and where R is either hydro gen or a benzyl radical (C,,H,-,CH.

More particularly, this invention relates to novel intermediates produced in the synthesis of the above compounds and to processes for making these intermediates.

BRIEF SUMMARY OF THE INVENTION This invention is directed to new and improved proeesscs for the chemical synthesis of the physiologically active macrolides known as zearalanes [I having the formula:

HO (CllzIx where X is an integer which may have the value l, 2. 3, 4, 5, 6, 7, 8, 9,10,11,12, or l3.

In the above formula, the letters A and B are used to denote the two different ring systems in the molecule. It will be noted that in the compounds known as zearalanes II. the carbon atom attached to the oxygen atom of the carboxyl group has no chirality since it is also attached to two identical atoms (hydrogen). A zearalane II compounds does not, therefore, exist in two isomeric forms. I

More particularly this invention relates to novel intermediates produced in the synthesis of the foregoing compounds and to processes for making these intermediates.

It is the object of the present invention to provide a' synthesis for new compounds known as zearalanes II which are related to zearalane.

It is another object of the present invention to provide syntheses for the zearalanes II as well as for certain of their derivatives.

It is a further object of the present invention to provide new processes for making intermediate compounds useful in the syntheses of the zearalanes II and their derivatives.

DETAILED DESCRIPTION CHART I "Reactions for the Chemical Synthesis of Norzearalane II" CHART II "Reactions for the Chemical Synthesis of zearalane II.

CHART III "Reactions for the Chemical Synthesis of the Tetrabenzyl Ether of the Dimeric Dilactone from 2,4Bis(benzyloxy)6- (5-hydroxypentyl) -benzoic Acld" All of the reactions have been found to proceed in a straightforward manner and they require nothing other than apparatus and equipment found in the conventional chemical laboratory.

A. Norzearalane II This compound has the formula OH O l l I! I 2 no (cs NOTE: 0 CH Cl designates benzyl chloride; NaOAc is sodium acetate CHART ll Reactions for the Chemical Synthesis of Zearalane ll NOTES: (a).CH Cl designates benzyl chloride; (b) NaOAc is sodium acetate: (c) XXA tetrahydroxy dimeric luctonei CHART 111 xxx! x c l o Tetrabenzyl ether of the Dimeric Dilactone from 2,4-Bis(benzyloxy)-6- (S-hydroxypentyD-benzoic acid NOTES: (a) QCH CI designates benzyl chloride: (b) NaOAc is sodium acetate The first step in the synthetic sequence is the reaction of IO-undecenal with malonic acid to prepare trans- 2,12-trideeadienoic acid followed by esterifieation of this acid with diazomethane. The methyl ester thus produced is reacted with ethyl acetoacetate under the influence of sodium ethoxide to yield the sodium salt of ethyl 6-(9-deceny])-B-dihydroresorcylate. Bromination of the dihydroresorcylate produces ethyl 3-bromo-6- (9-decenyl )-B-dihydroresorcylate which is then treated successively with sodium ethoxide; ethyl alcohol, and acid to give ethyl 6-( 9-decenyl)-B-resorcylate. The foregoing resorcylate is then reacted with benzyl chloride to prepare ethyl 6-(9-decenyl)-,8-resorcylate dibenzyl ether. The benzylated ester is treated successively with diborane, water, hydrogen peroxide, and sodium acetate solution to form the primary alcohol, ethyl 2,4-bis( benzyloxy )-6-( lO-hydr oxydecyl benzoate. This primary alcohol is then reacted with so dium ethoxide in a toluene menstruum to produce norzearalane Il dibenzyl ether and a by-product, the dimeric dilactone from 2,4-bis(benzyloxy)-6-( l0- hydroxydecyU-benzoic acid. Hydrogenation of norzearalane II dibenzyl ether under one atmosphere pressure of hydrogen and at room temperature using a palladium on charcoal catalyst yields norzearalane ll.

B. Zearalane [I Zearalane II is represented by the formula on 0 C To start the sequence of reactions for the synthesis of zearalane ll, lO-undecenol- 1-01 is reacted with paratoluenesulfonyl chloride to give IO-undecen-l-yl p-toluene-sulfonate which is then treated with sodium bromide in a methanol menstruum to produce 1- bromo-lO-undecene The foregoing bromo compound is subjected to a Grignard reaction with triethyl orthoformate to prepare 1 l-dodecenal which is reacted with malonic acid to yield trans-2,13-tetradecadienoic acid. The foregoing acid is reacted with diazomethane to produce the methyl ester which on treatment with ethyl acetoacetate in the presence of sodium ethoxide yields the sodium salt of ethyl 6-( lO-undecenyl)-,B-dihydr0resorcylate. The dihydroresorcylate is brominated to prepare ethyl 3-bromo-6-( l()-undecenyl)-,B-dihydroresorcylate which is treated successively with sodium ethox ide and sulfuric acid to give ethyl 6-( lO-undecenyU-B- resorcylatc. This resorcylic ester is benzylated using benzy] chloride and the resulting ethyl 6-( l0- undecenyl)-,8resorcylate dibenzyl ether is subjected successively to the reagents diborane, water. sodium acetate, and hydrogen peroxide to give the primary'al- 2,4-bis( benzyloxy)-6( l l-hydroxyum 1 decyl)-benzoate. The foregoing benzoater is reacted cohol, ethyl with sodium ethoxide to effect a ring closure. and produce zearalane II dibenzyl ether and a byproduct the dimeric dilactone from 2,4bis(benzyloxy)-6-( l lhydroxyundecylj-bcnzoic acid. Hydrogenation of the foregoing ring compounds produces zearalane II and the dimeric dilactone from 6-(1 l-hydroxyundecyU-B- resorcylic acid.

C. Tetrabenzyl Ether of the Dimeric Dilactone from 2,4-Bis( benzyloxy )-6-( S-Hydroxypentyl )-Benzoic Acid This compound has the formula The initial step in the synthesis of the above dimeric lactone is the pyrolysis at 380C of 3-hydroxy-,l,5- hexadiene to yield S-hexenal. The foregoing aldehdye is reacted with malonic acid to give 2,7-octadienoic methyl resorcylate is converted to the ethyl ester by an interchange reaction with ethanol under the influence of sodium ethoxide. The ethyl resorcylate is reacted with benzyl chloride to yield ethyl 6-(4-pentenyl)-B- resorcylate dibenzyl ether. The benzylated resorcylate Value of "X" is then subjected sucessively to the action of diborane, water, sodium acetate solution, and hydrogen peroxide to prepare ethyl 2,4-bis(benzyloxy)-6-(5-hydroxypentyl)-benzoate. The foregoing ethyl benzoate is treated acid which on treatment th diazomethahe yields the 5 with sodium ethoxide in a toluene menstruum to effect methyl ester. The methyl ester iS reacted With ethyl aca ring closure and yield the dimeric dilactone of 2,4- etoacetate under the influence of sodium methoxide in bis-( benzyloxy)-6-(5-hydroxypentyl)-benzoic acid teta methanol menstruum to produce the sodium salt of b l h methyl -p y )-fiy y This Salt In the three reaction sequences exhibited in Charts 1, is bmminated to P p methyl 10 I], and III, there is considerable diversity in the prodp n nyl)-B- y y which is treated ucts obtained because of a variation in the tendency of cessively with sodium methoxide and sulfuric acid to the primal-y alcohols v11 XIX, and XXX] to f pr du methyl -p y )-fiy The nomeric compounds. The reactions of these alcohols to form monomer and dimer are shown below.

OCH2-C6H5 ll CH c 3 l o (cn -c-on I I CH2 H l C6H5 I o-cnz-c n o-cn -c n I o o ll g fis s C C o a (crm o-cnz 0 H l /C\ $31: (CHglx H O-fi (CHzl (3H2 0 0 CH2 C6115 (:ZHZ C6H5 6 5 Whether monomer or dimer predominates, depends on the characteristics of the B-ring which is to be formed to give the monomer. Table I lists the various 45 B-rings and indicates those in which monomer formation is most favorable.

TABLE I Arbitrary Scale of Tendency of Alkyl 2 ,4-Bis (benzy1oxy)-6( (X+l) -Hydroxyalkyl)1- benzoates to Form Monomers a Number of Atoms in B-Ring of Monomer 2,3,4 or 5 7, 8, 9, or 10 0 6 or 'I 11 or 12 V 2 The compounds produced by the process of this invention are useful in promoting the growth rate of meat-producing animals. The compounds can be administered to animals by any suitable method including subcutaneous injection of pellets under the skin of the ears of mammals as well as by oral and parenteral administrations. For example, the compounds can be formulated into pellets and put under the skin of the ear by a suitable gun or they can be suspended in a medium such as peanut oil and injected parenterally. The compounds can also be blended with ordinary feed containing nutritional values in an amount sufficient to produce the desired rate of growth and can thus be fed directly to animals.

When the compounds are to be fed directly to animals, the feed composition can be preparedcontaining the usual nutritionally balanced quantities of fats, carbohydrates, proteins, vitamins, and minerals together with the chosen compound. Some of these usual dietary elements are grains, such as ground grain and grain byproducts; animal protein substances such as those found in fish meal and meat scraps; animal and vegetable fats; vegetable proteins like soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; antibiotic supplements such as zinc bacitracin feed grade; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle includes alfalfa hay and ground corn cobs together with supplementary an tibiotics and vitaminaceous materials if desired.

The amount of compounds administeredto the animal, of course, depends upon the specific animal, its age and sex, and the desired rate of growth. Usually,

i IO-undecenal administration of from about l'to about 100 mg of a compound per animal per day produces significantly increased growth rate.

The following examples serve to illustrate the invention and set forth the best mode contemplated by the inventors for carrying out the invention.

The abbreviations used in the following examples are described in these paragraphs. The description of a nuclear magnetic resonance (nmr) scan is identified by the letters nmr followed by the solvent and reference substance placed in parenthesis; thus, nmr (CDCL TMS) means that the scan was made with deuterated chloroform as the solvent and tetramethylsilane as the reference substance. The position of the identified peaks may be described by the value:

6 cycles per second from TMS divided by 60 (This relation applies with a 60 megaherz instrument) 8 c.p.s. 60

or by r= ten minus 6 (10-8) The type of peak is shown by the first letter of the word describing the peak and is followed by a numeral indicating the number of hydrogen atoms involved. Examples are as follows:

singlet, one hydrogen 5,2 I singlet, two hydrogens (1,1 doublet, one hydrogen t,2 triplet, two hydrogens rn,4 multiplet, four hydrogens bread 3,]. a broad singlet for one hydrogen which may result from 05, coog, Cl l 0.

Coupling constants are valuable for identification of the positions of hydrogen atoms and with repsect to variations of the electronic environments. The coupling constants are measured as the distance between the peaks in question on the x-axis of the scan and are recorded as J values in terms of c.p.s.

Cycles per second are denoted by c.p.s. and by Hz.

In all of the examples, the temperatures are in degrees centigrade. In the nmr data, TMS is tetramethylsilane; DSS is sodium 2,2-dimethyl-2-si1apentane-5- sulfonate.

EXAMPLE 1 Example 1 shows the preparation of trans-2,12- tridecadienoic acid by the following general reaction wherein X 9:

. o coon fi z on; Heat cu I Pyridine a I n coon I 2) (x-1) 'malonic CH aicid I I. c=o

trans-2,1Z-tridecadienoic Acid I. A reaction mixture containing 100.8 g, 0.599 mol, of IO-undecenal, 41.6 g, 0.398 mol, of malonic acid and g of pyridine was stirred at 25 for 24 hr under nitrogen. After an additional 41.6 g of malonic acid was added, it was again stirred for another 24 hr at 25C. Then it was heated on a steam bath until carbon dioxide evolution ceased 12 hr). It was diluted with water (250 ml), and the resulting mixture was extracted with ether (3 X 200 ml). The

ether extract was washed with dilute hydrochloric acid (2 N, 4 X 50 ml), with water, and then dried (MgSO Its distillation gave unreacted IO-undecenal (bp 40 at 1.0 mm), and then 96.3 g, 0.458 mol (76%), of 1: bp l64-65 (0.1 mm); nmr (CDC1 TMS) 8 12.66 (s, 1, C005), 7.22 and 6.96 21, 1, J 15.7 Hz, J, 7 Hz,C1-l CH=C1-1), 5.93 and 5.67 (2 t, 1 ,J 15.7 Hz, J 1 Hz, CHCO), 5.72 4.92 and 4.88, (3 m, 3, typical CH =CH), 2.08 (br m, 4, CH CH=C), and 1.35 ppm (bf m, 12, gCHZ).

EXAMPLE 2 hr. After the reaction mixture was cooled to the solid that had precipitated was removed on a filter and was washed with ether until it was white to give 89.2 g, 0.262 mol (84%), of the sodium salt Ill: nmr (D 0,

Methyl trans-2,l2-Tridecadienoate 11. A solution of diazomethane in ether was added to a stirred, cold (0) solution of 95.0 g, 0.454 mol, of I in 150 ml of ether untilthe yellow color persisted. The ether was evaporated to give 104.0 g of the crude ester, that was distilled with a Nestor-Faust spinning band fractionating column togive 96.7 g, 0.422 mo! (93%) of 11: bp 112ll3 (0.4 mm); nmr (CDCl TMS) 87.07 and 6.81 (2 t, 1. .1 15.7 Hz, J 7 Hz, CH- CH=CH), 5.91 and 5.65 (2 t. 1,1 15.7 Hz, J l HZ, CHCO), 5.72, 4.92 and 4.88 (3 m, 3, CH CH), 3.66 (s, 3. OCHQ). 2.12 (br m, 4, CH CH=C) and 1.34 ppm (br m, 12. CH. ,(CH CH EXAMPLE 3 Example 3 exhibits the preparation of ethyl 6-(9- decenyl),8dihydroresorcylate and its sodium salt by the following general reaction wherein X 9:

III

with stirring under nitrogen. This reaction mixture was held at reflux while 72.3 g, 0.323 mol, of 11 also was added dropwise over 1 hr, and then it was stirred for 20 DSS) 85.72, 4.92 and 4.88 (3 m, 3 CH =CH),4.22 (q,

2, J 7 Hz, COOCH 3.18 and 2.20 (2 m, 3, ring tau- I tomers), (br m, 2, CH CH=CH and 1.28 ppm (br m,

18. C1-1(CH CH and CH A solution of 3.00 g, 0.00872 mol, of III in ml of water was made acidic with hydrochloric acid (3 N). The resulting mixture was extracted with ether (4 X 25 ml). The other solution was washed with water (4 25 ml), and dried (MgSO It was evaporated to give a residue that crystallized from ligroin (bp 68) to yield 2.28 g, 0.00706 mo] (81%) of the B-dihydroresorcylate from 111: mp 5960; nmr (CDC1 TMS) 86.80 (5, ca. 1, tautomeric hydroxyl), 5.72, 4.92 and 4.88 (3 m, 3, typical CH=CH. 4.20 (q, 2, J 7 Hz, COOCH 5.52, 3.15, 3.1.2 and 2.46 (4 m, ca. 4, ring tautomcrs), 2.06 (br m, 2, CH CH=CH 1.32 (br m,

15, CH(CH CH2). and 1.28 ppm (t, 3, J 7 Hz, CH Anal. Calcd. for C,,,H ,O C, 70.8; H, 9.4.

35 Found: C, 70.6; H, 9.5.

c-o-c u EXAMPLE 4 1n Example 4, ethyl 3-bromo-6-(9-decenyl)-B-dihydroresorcylate is produced by the following general reaction wherein X 9:

I C2115 Br 12 2 5 (C112) 0 -1 CH=C112 Ethyl 3-bromo'6-( 9-decenyl )-,8-dihydroresorcylate IV. A solution of 16.7 g, 0.104 mol, of bromine and 60.0 g, 0.58 moi, of sodium bromide in 200 ml of water was added dropwise over 4 hr to one of 34.5 g, 0.100 mol, of the sodium salt [11 in 700 ml of water that was stirred rapidly at After 15 minutes of additional stirring, the floceulent solid that had precipitated was collected on a filter. It was dissolved in 200 ml ether, the other solution was washed with water (3 X 75 ml), and briefly dried (MgSO discolored with longer drying time). The ether solution was evaporated in a vacuum rotary evaporator (Rinco), and the residual product was recrystallized from 200 ml of ligroin (bp 3060) to give 26.0 g, 0.0648 mol (65%), of white IV: mp 93-94; nmr (CDCL, TMS) 86.70 (br, 5, ca. 1, 4-OH), 5.72, 4.92 and 4.88 (3 m, 3, CH =CH), 4.22 (q, 2, J 7 Hz, COOCH 3.35, 2.72 and 2.43 (3 m, ca. 3, ring tautomers), 2.06 (br m, 2 CH CH=CH and 1.30 ppm (br m, 18, CH(CH CH and CH Anal. Calcd. for C ,,H O Br: C, 56.9; H, 7.3; Br, 19.9 Found: C, 56.6; H, 7.3; Br. 20.2.

In Example 4, the temperature at which the reaction of bromine with Compound [11 is allowed to occur is kept at 0C in order to minimize the reaction of bromine with the double bond in the side chain of the com pound. Temperatures up to 25C could be used for this reaction but 0C is preferred. A lower temperature limit of about -l0C is set since the rate of the desired reaction becomes too low at temperatures much below l 0C, and the reaction mixture would probably freeze solid at temperatures much below l()C.

EXAMPLE 5 111 Example 5, ethyl 6-(9-decenyl)-,B-resorcylate is prepared by the following general reactions wherein X Br C-O-C2H5 CzllgONa HCl HO (CH2) (x-1)-CH=C1I2 HO IV V lene chloride), and recrystallization from ligroin (bp 60), gave 19.0 g, 0.0594 mol (53%) of pure V: mp 45.546.5; nmr (CDC1 TMS) 511.88 (s, l, hydrogen-bonded 2-OH), 7.15 (br s, 1, 4-OH), 6.33 and 6.30 (2 d, 2, J 2 Hz, aromatic CH), 5.72, 4.92 and 4.88 (3 m, 3, CH- CH), 4.40 (q, 2, J =7 Hz, COOCH 2.83 (t, 2, .1 6 Hz, ArCl-l 2.0O (m, 2, CH CH=C), 1.40 (t, 3, .I 7 Hz, CH and 1.32 ppm (m, 12, CH (CH ),,CH- Anal. Calcd. for C19H2gO4: C, 71.2; H, 8.8 Found: C, 71.0; H, 0.6.

In example 5 the dehydrobromination of compound IV can be effected at temperatures in the range 60120C but a temperature near 80C is preferred. At a temperature of 80C. the rate of dehydrobromination is reasonably fast.

The dehydrobromination step could be carried out in a menstruum of an alcohol than ethanol, for example methanol or butanol.

EXAMPLE 6 In Example 6, ethyl 6-(9-deeenyl)-B-resorcylate dibenzyl ether is formed by the following general reaction wherein X 9:

Ethyl 6-(9-decenyl)62 -resorcylate Dibenzyl Ether VI. A reaction mixture containing 9.00 g, 0.0281 mol, of V, 10.9 ml. 0.08972 mol, of benzyl chloride, and 20 g of anhydrous potassium carbonate in 150 ml of dried C O-c 11 Et y dec y )-B-rcs0 y g. 11-112 (MgSO Solvents were evaporated under vacuum to mol, of 1V in a sodium ethoxide solution (prepared from 20.00 g, 0.870 g-atom, of sodium in 500 ml anhydrous ethanol) was held at reflux under nitrogen for 3 hr. Then. about 400 ml of ethanol was evaporated under vacuum. The reaction mixture was dilutedwith water to 500 diluted with while it was cooled in ice, and then it was acidified with hydrochloric acid (6 N). It was extracted with ether (3 X 20() ml), and the extract was washed with water (4 X 200 ml) until these washings were neutral to pH paper. This orange solution was decolorized with charcoal, and the ether was evaporated to yield 34.1 g (9571 of crude V. A dry column chromatographic separation (680 g Silica Gel H heated before use at 1 10 for 14 hr, 1071 ethyl ether in methy give 13.0 g, 0.0260 mol (92% of V1 that had the expected nmr spectrum; nmr (CDCl TMS) 67.24 (m, 10, C,;H.-,). .41 (s, 2. aromatic CH), 5.72, 4.92 and 4.88 (3 m. 3. CH=CH. 4.90 and 4.87 (2 s, 4, benzyl CH 4.25 (q. 2, J 7 Hz, COOCH 2.58 (t, 2, 1 6H2, ArCH- 2.00 (m, 2, CH CH=C), 1.28 (br m, 12, CH (CH ),,CH. and 1.18 ppm (t, 3, J 7 Hz, CH

EXAMPLE 7 in Example 7. ethyl 2,4-bis(ben7.yloxy)-6-( l0- hydroxydeeyl)-benzoate is made by the following general reactions where X 9:

Ethyl zoate, Vll. Ten ml of 0.93 M-diborane (0.0093 mol) in tetrahydrofuran was dropped slowly into a stirred solution of 7.5 g (0.015 mol) of VI in 100 ml of the same solvent held at under nitrogen. Stirring was continued for 1 hr at 0 and for 4 hr at 25. Then the reaction mixture was held at 0 while ml of water, 5 ml of 3 M-sodium acetate, and 8.5 ml of 30% hydrogen peroxide were successively added to it dropwise. After subsequent stirring for 1 hr, 200 ml of ether was added. The ether phase was separated, and the aqueous one was extracted with ether (2 X 100 ml). The ether extract CH2CISHS was washed with saturated brine, and then dried (MgSO lts evaporation gave 6.8 g of crude Vll: yellow oil; tle (9 CH Cl zl Ether) major spot R, 0.65, and two minor ones R 0.23 and 0.34; nmr (CDCl TMS) 67.30 (s, 10, C H CH 6.42 (s, 2, resorcylate CH), 4.95 (s, 4, C,;H -,CH 4.28 (q, 2, CH:,CH. .O), 3.58 (m, 2, CH OH), 2.58 (m, 2, ArCH. and L28 ppm (m, 19, CH -,CH O and CH 2,4-bis( benzyloxy )-6-( ltl-hydroxydeeyl )ben-.

EXAMPLE 8 In Example 8, norzearalane dibenzyl ether and the dimeric dilactone tetrabenzyl ether are made by the following general reaction wherein X 9:

water was added to it. Dilute hydrochloric acid was added until the aqueous phase was acidic. The toluene solution was separated and combined with ether extracts (2 X 100 ml) of the aqueous phase. This organic solution was washed with saturated brine, and dried (MgSO Evaporation gave 6.5 g of a yellow paste. lts solution in 24 ml of ether was held at 2() for 12 hr, and 1.4 g of a white solid crystallized. The solid was recovered on a filter and was washed with ether. The product in the ether filtrate was used to prepare 1X (see Example 9). Since the mass spectrum of the 1.4 g of solid indicated that it contained some dimeric dilactone tetrabenzyl ether VlllA (parent mass 944), it was purified by dry column chromatography (Silica gel H, 9 CH C1 :1 ether). The tle of the crude product showed some material at the origin with a major spot at R 0.74. All chromatographic fractions that contained only the latter (tlc) were combined and evaporated. Recrystallization of the residue from chloroform pentane gave V111: mp 126127, 1.0 g, nmr (CDCl TMS) 57.36 (s, 1(). C H CH 6.44 (s, 2. ArCH), 5.02 (s, 4, C,;H,-,CH. 4.28 (t, 2, J 5.5 Hz, CH O); 2.58 (m, 2, ArCH and 2.0l1.1 with peak at 1.29 ppm (m, 16, CH mass spectrum (70 eV) m/e (relative intensity) 472 (3.6), 454 (3.3), 382 (6.7), 364 (7.8). 293 (2.5), 275 (2.8). 181 (6.1), 180 (5.0), 91 (100), 65 (7.8), 63 (3.0). 55 (2.9). 41 (4.3), 39 (3.6).

Anal. Calcd. for C;,,H;, ;O C. 78.78; H, 7.68. Found: C,

In Example 8. ring closure of compound V1] is ef fected by heating the compound in a dry menstruum which is initially ethanol-toluene and which becomes toluene in the latter stages of the operation at a temperature in the range 75l C. This temperature range could be lowered somewhat but the reaction becomes very slow below 60C. Temperatures above 1 10C can be used but at temperatures much beyond 120C undesirable reactions occur.

EXAMPLE 9 Example 9 shows the preparation of norzearalane dibenzyl ether by the following general reaction wherein Norzearalane 11, [X The other solution from Example 8 was evaporated to give 5.1 g of crude V111. A mixture of it with 50 ml of ethanol. 50 ml of ethyl acetate.

and 1.5 g of 107! palladium on charcoal with three drops of triethylamine was hydrogenated at 25 and 1 atm until hydrogen consumption (0.022 mol) ceased. The reaction mixture was filtered. and the filtrate was evaporated to yield a brown semisolid. Dry column chromatography (9 CH CI H ether, silica Gel H) gave early fractions that contained a single substance (tlc, RF 0.62), and their evaporation gave 1.2 g (0.004) mol, 35% yield from VI) of crystalline solid.

lts recrystallization from ehloroformpentane gave pure 1X, mp 150-151; 0.45 g; nmr (CD COCD TMS) 511.62 (s, 1, 2OH),6.32 (d, 1, .1 2 Hz, ArCH), 6.24 (d, 1, J 2 Hz. ArCH), 4.40 (m, 2. CH- O), 3.20 (bs, 1, 4OH), 2.83 (m, 2, ArCH and -l.9l.1 with peak 1.42 ppm (m, 16 -CH mass spectrum eV) m/e (relative intensity) 292 197(14), 178(18),177(22),168(76),164(28), 163 (44), 151 (23), (60), 124 (25), 69 (24), 55 (33), 41 (35 Anal. Calcd. for C H O C, 69.83; H, 8.27. Found: C, 69.78; H, 8.24.

EXAMPLE 10 In Example 10, undecen-l-yl) p-toluenesulfonate is made by the following general reaction wherein X llLundcecn- 1 -ol X IO-Undeeen-l-yl p-toluenesulfonate X. To a stirred solution of 100.0 g, 0.538 mol, of lO-undecen-l-ol in ml of pyridine by calcium chloride drying tube and cooled in an ice bath, 123.1 g, 0.646 mol, of ptoluenesulfonyl chloride was added at a rate that maintained the temperature below 10. After this reaction mixture had been stirred at room temperature for 3 hr, it was acidified with 3 N hydrochloric acid while it was held at 0. It was then extracted with ether (3 X 400 ml) and the extract was washed with water (5 X 200 ml). The ether solution was dried (MgSO and the solvent was removed under vacuum to yield 163.9 g, 0.505 mol (94% of X: nmr (CDCl TMS) 57.76 (d, 2, .1 8 Hz, aromatic CH), 7.31 (d, 2, J 8 Hz, aromatic CH), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH-,), 4.00 (t, 2, .1

6 Hz, CH- OS). 2.36 (s, 3. CH CH CH=CH and 1.23 ppm CH (CH- CH 1.87 (br m, 2, (br m, 14,

EXAMPLE 1 1 l-Bromo-lO-undeeene XI. A solution of 165.00 g, 0.509 mol, of X and 62.4 g, 0.607 mol of sodium bromide in 600 ml of methanol (dried by distillation from sodium methoxide) was distilled until 50 ml of the methanol had been removed, and then it was maintained under nitrogen at reflux for 6 hr. The solvent was removed under vacuum, 500 ml of water was added to the residue, and the organic layer was extracted into ether (3 X 500 ml). This extract was washed with water (3 X 300 ml), dried (MgSO,), and evaporated to yield 1 10.0 g of a residue that was fractionally distilled to give 88.0 g, 0.378 mol, (75%) of XI: bp 7677(0.10 mm); nmr (CDC1 TMS) 85.72, 4.92 and 4.88 (3 m, 3, CH=CH 3.37 (t, 2, J 7 Hz, CH Br), 2.00 (br m, 2, CH CH=CH and 1.33 ppm (br m, 14, CH (CH CH EXAMPLE 1 2 Example 12 exhibits the preparation of l l-dodecenal by the following general reactions wherein X 10:

1 l-Dodecenal XII. With the usual procedure for the preparation of a Grignard reagent, a solution of 169.3 g, 0.727 mol, of X1 in 500 ml of anhydrous ether was added to 21.2 g, 0.872 g-atom, of magnesium turnings with stirring. After the addition was complete, the reaction mixture was held at reflux for 2 hr. Then, a solu tion of 161.7 g, 1.09 mol, of triethylorthoformate (dried by distillation) in 200 ml of anhydrous ether was added over 1 hr while the reaction mixture was held at reflux. It was held at reflux for an additional hr. Finally, it was cooled to 0 and stirred while 300 ml of 3 N sulfuric acid was added to it. The ether layer was separated, and the aqueous phase was extracted with ether (2 X 200 ml). The ether extract was washed once with water, and then it was evaporated. The residual product was treated with 200 ml of 3 N sulfuric acid, and

the mixture was heated on a steam bath with stirring for 3 hr. It then was extracted with ether (3 X 150 ml). The extract was washed with water until these washings were neutral, and then was dried (MgSO.,). Distillation 1.96 (br m, 2, (br m, 1 4,

EXAMPLE 1 3 In Example 13, trans-2,13-tetradecadienoic acid is produced by the following general reaction wherein X 1"" 1 CH COOH CH I 2) l.\' u 2 I: u 1) CH0 COOH (III'H XII (TH COOH XIII

Preparation of trans-2, l 3-tetradecadienoic acid XIII. A reaction mixture containing 63.31 g, 0.348 mol, of XII, 39.80 g, 0.383 mol, of malonic acid and ml of pyridine was stirred at 25 under nitrogen for 109 hr, and then it was heated on a steam bath until carbon dioxide evolution ceased (13 hr). Water (75 ml) was added to it, and the resulting mixture was extracted with ether (2 X 200 ml). The extract was washed with dilute hydrochloric acid (2 N, 2 X 50 ml), with water, and then dried (Na SO Its distillation gave 56.77 g, 0.253 mo], (73%) of trans-2,13-tetradecadienoic acid XIII: bp l40141 (0.09 mm); N 1.4741; nmr (CDCl TMS) 811.54 (s, 1, COOH), 7.26 and 7.00 (2 t, 1, 1 15.7 Hz, J 7 Hz, CH CH=CHCO), 5.98. and 5.70 (2 t, 1, J 15.7 Hz, I 1 Hz, CHCO, 5.72, 4.92 and 4.88 (3 m, 3, CH=CH. 2.12 (br m, 4, CH CH=C), and 1.32 ppm (br m, 14, CH (CH CH Anal. Calcd. for C H- O- C, 75.0; H, 10.8. Found: C, 75.0; H, 10.9.

EXAMPLE 14 In Example 14, methyl trans-2,13-tetradecadienoate is prepared by the following general reaction wherein X 10:

Methyl trans-2. 1 3-tetradeeadienoate XIV. A solution of diazomethane in ether was added to a stirred, cold (0) solution of 56.77 g. 0.253 mol, of XIII in ml of ether until its yellow color persisted. The ether was then evaporated to give 58.0 g of crude ester. Its fractional distillation gave 52.89 g. 0.222 mol, (88%), of

XIV: bp l20l23 (0.35 mm); n,, 1.486; nmr Ethyl 3-bromo6( IO-undecenyl)B-dihydroresorcy- (CDCI TMS) 67.04 and 6.78 (2 t, l. J 15.7 Hz, late XVI. A solution prepared from 15.18 g, 0.0950

J 7 HZ, CH CH= CHCO), 5.87 and 5.61 (2 t, l. J mol, of bromine and 51.5 g, 0.500 mol, of sodium bro- 15.7 Hz, J 1 Hz, CH=CHCO), 5.72. 4.92 and mide and 200 ml of water was added dropwise over 6 4.88 (3 m, 3, CH=CH- 3.67 (s, 3, CH 2.12 (br m, 5 hr to a rapidly stirred one of 34.00 g, 0.0950 mol, of 4, CH CH=C), and 1.30 ppm (br m, 14, XV in 800 ml of water that was held at The color CH (CH CH Anal. Calcd. for C H O z C, 75,6; of the bromine solution was discharged as it was added,

H, l 1.0. Found: C, 75.8; H, l 1.2. and a white solid precipitated. It was collected on a filter, and then was dissolved in 200 ml of ether. The

EXAMPLE l l0 ether solution was washed with water (3 X 75 ml), and

In Example 15. the sodium salt of ethyl 6-( l0- briefly dried (MgSO This solvent was evaporated, undecenyl)-/3-dihydroresorcylate is formed by the fol and the residue wasrecrystallized from 200 ml of ether lowing general reaction wherein X to give 26.10 g, 0.0627 mol. (66%) of white XVI: mp

+ 2) n z a CH, CH

XIV XV The sodium salt of ethyl 6-(l0-undecenyl)-,B-dihy- 7880; nmr (CDCI TMS) 67.86 (5, ca. 1, 4OH), droresorcylate XV. When the reaction of 6.14 g, 0.267 5.72, 4.92 and 4.88 3 m, 3, CH= CH 4.22 (q, 2, J mol, ofsodium in 87 ml ofanhydrous ethanol was com- 7 H COOCH 3,35, 2,72 a d 2,43 (3 m, ca, 3, ring plete, 34.7 g, 0.267 mol, offreshly-distilled ethyl aceto' CH of tautomers), 2.06 (br m, 2, CH CH=CH and acetate was added dropwise with stirring under nitro- 1.30 ppm (br m, 20, CH(CH ),,CH and CH Anal. gen. Then, the reaction mixture was stirred at reflux Calcd. for C H O Br: C, 57.8; H, 7.5, Br, 19.3. while 52.89 g, 0.222 mol, of XIV was added to it drop- F nd; C, 57.4; H, 7.5; Br. 19.6. wise. As it was heated for an additional 22 hr and was I E l 16, th t rature at hi h the reaction subsequently cooled to 0, 21 id precipitated. It as of bromine with compound XV is allowed to occur is recovered on a filter, and it was washed with ether until k t at 0C in order to minimize the reaction of bro it as Whit t gi -36 g of Additional Such mine with the double bond in the side chain ofthe comsolid precipitated when 50 ml of ether was added to the d, Tem rature u to 25C could be used for this fi trat g 21 10ml of 62-94 g, 0-176 Of reaction but 0C is preferred. A lower temperature XV: nmr 2 and limit of about -l0C is set since the rate of the desired H= (q. J 7 zL l 8 reaction becomes too low at temperatures much below n 2 ng tautomers), (br m, 2, l0C, and the reaction mixture would tend to freeze 2 2L and pp 2)g solid at temperatures much below -lOC. and CH EXAMPLE l6 EXAMPLE l7 EXumple 1 Sets fOrth h n rl f r ing ethyl Example 17 illustrates the preparation of ethyl 6-( l0- r 1 n ny )-B- ihy y y undecenyU-B-resorcylate by the following general rethe following general reaction wherein X 10: 5 ti h i X 10:

XVI XVII Ethyl 6-( lO-undecenyl)-B-resorcylate XVII. A sodium ethoxide solution was prepared from 12.10 g, 0.527 g-atom, of sodium in 300 ml of anhydrous ethanol, 48.49 g, 0.1 17 mol of XVI was added to it, and the mixture was held at reflux under nitrogen for 4 hr. 5 washed with water (8 X 100 ml), and dried (MgSO About 200 ml of ethanol was evaporated. The residual E a oratio u d uum ga 28,() g, ()543 l mixture was held at while 400 ml of water was adde (91%) of XVIII with the expected nmr spectrum; nmr to it, and then it was acidified with 6N sulfuric acid. It (cDcl TMS) 57 24 10 (1 1-1 641 (S, 2 was extracted with ether (3 X 200 ml) and the extract aromati CH), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH was washed with water (4 X 200 ml) until these wash- 490 and 437 2 s, 4 CHI-1.5GHz), 42 (q, 2 J 7 HZ, ings were neutral to pH paper. The resulting orange So- COOCH2), -58 (t, 2, J H A cl-l 197 (m, 2 lution was decolorized with charcoal, and the ether was C C =CH2 2 (b m, 14 CH2(CH2)7CH2), and evaporated to yield 37.06 g, 0.111 mol, (95%) ofcrude L18 ppm (t, 3 j -1 CH3). product. Dry column chromatography (750 g Silica Gel H, 10% ethyl ether in methylene chloride) and the re- EXAMPLE l9 crystallization of appropriate fractions from ligroin (bp 1 Example 19 ethyl g 4 i 1 1- g, 0-0680 (58%) of P XVII? hydr0xyundecyl)-benzoate is produced by the followmp 565 nmr TMS) 81192 (S, ing general reactions wherein X 10: 2-OH), 7.64 (br s, l, 4=OH), 6.33 and 6.30 (2 d, 2,

OCH2C.;H OCH. ,-C,;H,=,

O I? O 32H" COC'-H-" 2 Hz, aromatic CH), 5.72, 4.92 and 4.88 (3 m, 3, Ethyl 2,4-bis(benzyloxy)-6-( l l-hydroxyundecyl)- CH=CH 4.40 (q, 2, J 7 Hz, COQCH 2.84 (t, 2, benzoate, XIX. Over a period of min, 13.0 ml of J 6 Hz, ArCl-l 2.03 (m, 2, CH CH=CH 1.40 (t, 0.93 M-diborane (0.012 mol) in tetrahydrofuran was J 7 3) and pp 2( 2 )7 35 added dropwise to a solution of 10.28 g (0.020 mol) of 2)- Analcalcd for 20 30 4 C, H, .0. XVIII in 50 ml of tetrahydrofuran stirred at 0 under ni- Found: 71-5; I trogen. A further 1 hr at 0 and 4 hr at 25 was allowed.

In Example the dehydrobrommanon Then 10 ml of water was added over 10 min. After the pound E l effected at ggj i the addition of 20 ml of 3 Nsodium acetate solution, 20 ml range 60 C ]2O but atemPeZawre near ls pm 40 of 30% hydrogen peroxide solution was dropped in ferred. At a temperature of 80 C the rate of dehydro- 20 m n 1 nd he eact n m tu e was Stirred for bromination is reasonably fast. Over f The dehydrobromination step could be carried out in another 30 It was extracted vfllth ether (5 a rncnstruum of an alcohol other than ethanol, for exf the extract was washed wlth Saturated brme ample methanol or butanoL and dried (MgS O Evaporation gave 9.5 g of a yellow oil. Although its thin layer chromatography showed EXAMPLE 1 that it contained two components (silica gel, 9 CH Clether, major R, 0.54 minor R, 0.32), the major one Example 18 exhibits the preparation of ethyl 6-( 10- was XIX; nmr (CDCI TMS) 87.27 (s, 10, undecenyl)-B-resorcylate dibenzyl ether by the follow- CGH5CH2 640 (s, 2 Arc), 492 (s, 4 ing general reactions wherein X 10:

Ethyl 6-( lO-undecenyl)-B-rcsorcylatc dibenzyl other XVlll. A reaction mixture containing 20.00 g, 0.0598 mol, of XVll, 40 g of anhydrous potassium carbonate, and 20.0 ml, ().l74 mol, of benzyl chloride in 300 ml of dry dimethyl sulfoxide was stirred and heated on a steam bath for 6 hr. Then 1.0 l. of water was added to it, and the oil that separated was extracted with 1.0 l. of a solution of 50% ether in pentane. The extract was EXAMPLE Example 20 exhibits the preparation of zearalane II 10 dibenzyl ether plus some dimeric dilactone tetrabenzyl ether by the following general reaction wherein X 10:

C Chg i O XX XXA 2,4Bis(benzyloxy)Zeara1ane II dibenzyl ether, XX. After excess ethanol has been distilled as the ethanoltoluene azeotrope, a reaction mixture containing 7.98 g (0.015 mol) of crude XIX, sodium ethoxide solution from 0.69 g (0.015 g atom) of sodium with 50 ml of ethanol, and 800 ml of toluene (dried over sodium) was held at reflux under nitrogen for 36 hr. Then it was cooled to 500 ml of water was added to it, and it was made acidic with dilute hydrochloric acid. The toluene solution was separated, and the aqueous phase was ex tracted with ether. Toluene and ether solutions were combined, washed with saturated brine and dried (MgSO Evaporation gave 7.5 g of a semisolid product mixture that contained three substances (tlc as above, major R, 0.67 and minor 11,031 and 0.18). Dry column chromatography as above gave a series of fractions R 0.67 that were evaporated to give 3.2 g (0.0065 mol, 447r assuming starting XIX pure) of white solid XX: mp 175-176 from ether-pentane; nmr (CDC1 TMS) 87.30 (s, 10, C I-I CH 6.42 (s, 2, ArCH), 4.97 (s, 4, C,,H CH 4.27 (t, 2, J 6.0 Hz, -CH O), 2.58 (m, 2, ArCH and l.9l.0-peak 1.28 ppm (m, 18, CH (CH CI-I mass spectrum eV) m/e (rel. intensity) 486 (2), 468 (2), 396(3), 378 (5), 307 (1), 289 (2), 181 (4), 180 (3), 128 (3), 127 (2), 92 (12), 91 65 (8), 63(3), 55(2), 51(2), 44 (5), 41 (3), 39 (4). Anal. Calcd. for C H 0 C, 78.98; H, 7.87. Found: C, 78.96; H, 7.95.

After the XX had been eluted, the column was washed with methanol. Evaporation of the methanol solution gave 4.5 g of a brown solid (mp 85102; mass spectrum showed dimer XX A parent ion 972). It was treated with excess sodium ethoxide in ethanol at 150 for 8 hr in a bomb tube. Workup gave a single product XIX (tlc and nmr).

In Example 20, ring closure of compound XIX is effected by heating the compound in a dry menstruum which is initially ethanol-toluene and which becomes toluene in the latter stages of the operation at a temperature in the range 60l20C., preferably 75110C. This temperature range could be lowered somewhat but the reaction becomes very slow below 60C. Temperatures above 1 10C can be used but at temperatures much beyond C undesirable reactions occur.

EXAMPLE 21 Example 21 shows the preparation of zearalane II by the following general reaction wherein X 10:

O CH. ,-C,,H

0 OH 0 ll 11 C\ C\ 0 H 0 1 CH. Pd on H.

I Charcoal CH. H. (CH-fi mn H() (CH2) |.\'u

XX XXI XXIA Zearalane II XXI. A solution of 2.5 g (0.051 mol) of XX in 20 ml of ethanol and 50 ml of ethyl acetate with 1.5 g of palladium on charcoal and a few drops of triethylamine was hydrogenated at 25 and 1 atm. When 260 ml (25) of hydrogen had been consumed after 2 hrs the reaction mixture was filtered. The filtrate was evaporated to give a yellow semisolid. Thin layer chromatography as above showed one major component (R 0.60) but some material remained at the origin. Its mass spectrum showed that dimer lactone XXI A (parent ion 612) was present. Dry

column chromatography gave 1.5 g of material- (tlc, R 0.60) that was then recrystallized from ether-pentane. The mp 121122 was sharp, but again its mass spectrum showed traces of dimer.

The recrystallized material was sublimed at 110 EXAMPLE 22 In Example 22, the compound 5-hexenal, XXII, is prepared by the pyrolysis of 3-1,5-hexadiene at a temperature of 380C.

S-Hexcnal, XXII. 190 g, 1.94 mol, of 3-hydroXy-1,5- hexadiene was slowly distilled through a 50 cm column packed with 3 mm Pyrex helices maintained at 380. Fractional distillation of the pyrolysis mixture gave 111.2 g, 1.14 mol (59 percent), of 5-hexenal: bp 57.5 (57 mm). The boiling point of this product is given as 12012 1 (760 mm) by Viola and Levassuer J. Amer. Chem. Soc. 87, 1150 (1965).

EXAMPLE 23 Example 23 gives the details of a method for preparing 2.7-octadienoic acid, XXIII, by the reaction of 5- hexenal. XXII, with malonic acid.

CH T COOH CH (flu, :i lfine 1 lz OOH H2 1 m 1 9 H (:H

f=o on XXIII 2,7-Oetadienoic acid XXIII. A reaction mixture containing 76.9 g, 0.784 mol, 5-hexenal XXII, 90.0 g,

30 0.865 mol, of malonic acid, and ml of pyridine was stirred at 25 under nitrogen for 60 hr. An additional 45.0 g of malonic acid was added to it, and stirring was continued for 24 hr at 25. It was then heated on a steam bath until carbon dioxide evolution ceased (20 hr). Water 145 ml) was added to it, and the resulting mixture was extracted with ether (3 X 200 ml). The extract was washed with dilute hydrochloric acid (2N, 2 X 50 ml), water (2 X 50 m1), and dried (Na SO Fractional distillation gave 83.0 g, 0.593 mo] (76 percent), of XXIII: bp 8687 (0.15 mm); nmr (CDCI TMS) 612.34 (s, 1, COOH), 7.26 and 6.98 (2 t, 1, .I,,,,= 15.7 Hz, J 7 Hz, CH CH==CH), 5.97 and 5.70 (2 t, 1, J 15.7 Hz, J 1 Hz, CHCOO), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH 2.12 (br m, 4, CH CH=CH), and

1.60 ppm (br m, 2, CH CH CH Anal. Calcd. for C H 0 C, 68.6; H, 8.6. Found: C, 68.6; H, 8.7.

EXAMPLE 24 In Example 24, methyl 2,7-octadienoate is prepared by the following general reaction wherein X 4:

Methyl 2,7-octadienoate XXIV. A solution of diazomethane in ether was added to a cold (0) solution of 83.0 g, 0.592 mol, of XXIII in 200 ml of ether until a yellow color persisted. Evaporation of the reaction mixture gave 90.3 g of crude XXIV that was fractionally distilled to give 80.2 g, 0.520 mol (88 percent) of XXIV: bp 4445 (0.70 mm); nmr (CDCM. TMS) 87.04 and 6.78 (2 t, l, .1 15.7 Hz, J =7 Hz, CH. ,CH=CH), 5.87 and 5.61 (2t,1, J 15.7 Hz, J, Hz, CHCO), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH. 3.67 (s, 3, CH 2.12 (br m, 4, CH CH==CH), and 1.58 ppm (br m, 2, CH CH CH- Anal. Calcd. for C H O C, 70.2; H, 9.1. Found: C, 70.1; H, 9.2.

EXAMPLE In Example 25, the sodium salt of ethyl 6-(4- pentenyl)-B-dihydroresorcylate and ethyl 6-(4 pentenyl)-,8-dihydroresorcylate are formed by the following general reactions wherein X 4:

2.00 (br m, 2, CH CH=CH 1.33 (br m, 5, CH(CH and 1.26 ppm (t, 3, J 7 Hz, CH

Then a solution of 3.00 g, 0.0109 mol, of XXV in ml of water was acidified with 3N hydrochloric acid and the resulting mixture was extracted with ether (4 X 25 ml). The extract was washed with water (4 X 25 ml), dried (MgSO and evaporated in a vacuum rotary evaporator (Rinco) to give a residue which crystallized from ligroin (bp -68), to give 2.37 g. 0.00942 mo] (86 percent), of ethyl 6-(4-pentenyl)-B-dihydrorcsorcylate XXV A: mp 72.5-73.5; nmr (CDCI TMS) 512.32 (s, 0.2, 2-OH), 9.75 (s, 0.8, 4-OH), 5.72, 4.92 and 4.88 (3 m, 3, CH CH 5.52 (s, 0.8, 3- CH), 4.29 and 4.22 (2 q. 2, J 7 Hz, COOCH 3.12

0 CH 0 0 l l l t| 0 c. .H (cu c o c,H CH (CH2), C H ONa l l C. .H,-,OH C CH ll 0 CH CH l 0 (CH2) \1 CH Na COOCH, l

Na H2 XXIV xxv o Xxv HCI fi-O-C H HO (CH i,CH=CH.

XXV A Q Sodium salt of ethyl 6-(4pentenyl)-,&dihydroresor- (s, 0.4, 3CH. 3.15 (d, 0.8, J 10 Hz, 1CH), 2.45 cylatc, XXV. 81.4 g, 0.626 mol, of freshly distilled (m, ca. 2, 5-CH 2.06 (br m, 2, CH CH=CH 1.36 ethyl acetoacetate was added dropwise to a stirred 50- (br m. 5, CH(CH ,-CH-, and 1.29 ppm (t, 3, J 7 Hz, lution of sodium ethoxide prepared from 14.4 g, 0.626 CH Anal. Calcd. for C I-M0 C, 66.7; H, 8.0. g-atom of sodium and 200 ml of ethanol under nitro' 40 Found: C, 66.7; H, 8.0.

gen. The resulting solution was held at reflux while 80.2 g, 0.521 mol, of XXIV was added dropwise, and then such heating was continued with mechanical stirring for 22 hr. The solid that precipitated during the reaction and while the mixture was cooled to 0 was re- 4 moved on a filter, and it was washed with ether to give EXAMPLE 26 Example 26 provides a method for the preparation of the sodium salt of methyl 6-(4-pentenyl)-B-dihydrore- 5 soreylate and of methyl 6-(4-pentenyl)-Bresorcylate by the following general reaction wherein X 4:

1? 1 o-c H ll n c o cH C (CHJH Em l l CHHOH c CH 0 CH,, H l 0 2)... ..CH=C

coocH, Na

XXVI 1 c-o -cH, XXVI HCI H0 (cra ..cH=cH.

XXVI A l 10.80 g, 0.404 mo] (78 percent), of white XXV: nmr

(D 0, DSS, integration of some ring hydrogen atoms not given since they exchanged) 55.72, 4.92 and 4.88 (3 m. 3. CH. ,=CH). 4.22 (q. 2. J 7 Hz. COOCH 3.18 (d, .1 10 Hz. HCCOO), 2.20 (m. OCCH CH).

Sodium salt of methyl 6-(4-pentenyl)-B-dihydrorcsorcylate, XXVI. The reaction mixture was prepared by dropwise addition of 70.7 g, 0.598 mol, of ethyl acetoacetate to a solution of 32.3 g, 0.598 mol, of sodium mcthoxide in ml of methanol stirred under nitrogen, and then 74.2 g, 0.482 mol, of XXIV was also mine with the double bond in the side chain of the comadded dropwise. It was held at reflux with mechanical pound. Temperatures up to 25C could be used for this stirring for 20 hr. About 60 ml of its solvent was rereaction but C is preferred. A lower temperature moved under vacuum, and it was cooled to 0. A prelimit of about l0C is set since the rate of the desired cipitate that formed during the above was removed on reaction becomes too low at temperatures much below a filter and washed with ether until it was white to give 1()C, and the reaction mixture would tend to freeze 4-7 g, @326 mol pe of XXVII nmr 2 solid at temperatures much below l0C. DSS): again exchange of hydrogen atoms on the ring occurred) 65.72, 4.92 and 4.88 3 m, 3, cn=cn, EXAMPLE 28 5.07 (s, OCCHCO), 3.18 (d, J Hz, HCCOO), 2.20 10 In Example 28, methyl 6-(4-pentenyl)/3-resorcylate (m, OCCH CH), 2.00 (br m, 2, (CH CH=CH and is produced by the following general reactions wherein 1.33 ppm (br m, 5, CH(CH CH The nmr spectrum X 4:

is nearly the same as XXV above, except for the Methyl 6-(4-p n eny )-Br ry XXVIII. A solualkoxy absorptions. tion of 21.5 g, 0.0678 mol, of XXVll and sodium methoxide (prepared from 15.6 g, 0.678 g-atom of sodium) E E 27 in 350 ml of anhydrous methanol was maintained at reflux under nitrogen for 9 hr. Then 200 ml of methanol Example 27 illustrates the preparation of methyl 3- 30 was evaporated under vacuum. The reaction mixture bromo-6-( 4-pentenyl)-B-dihydroresorcylate by the folwas held at 0 while enough water to give 400 ml of the lowing general reaction wherein X 4: mixture was added to it. It was acidified with sulfuric CO-CH;, Br COCH;,

H 0 0 H.) .,CH=CH. HO cH-...\--., H. Na

XXVI XXVll Methyl 3-bromo-6-(4-pentenyl)-Bdihydrores0rcyacid (6 N), and extracted with ether (3 X 200 ml). The

late XXVIl. A solution of 58.2 g, 0.326 mol, of bromine extract was washed with water (4 X 200 ml), and it was and 193.1 g, 187 mol, of sodium bromide in 200 ml of decolorized with charcoal, and evaporated (Rinco) to water was added dropwise over 6 hr to a rapidly stirred yield 14.9 g, 0.0632 mol (93 percent), of crude solution of 84.7 g, 0.326 mol, of XXVI in 700 ml of XXVlll. Purification by dry column chromatography water cooled to 0. After 30 min, the solid that had pre- (300 g, Silica Gel H, 10 percent ethyl ether in methycipitated was removed by filtration. It was dissolved in 6 16 C d yielded tions that gave product that 200 ml of ether, and the resulting solution was washed was recrystallized from ligroin (6068) to give 8.82 g, with water (3 X 150 ml), and briefly dried (MgSO It 0.0373 mo] percent), ofpure XXVIIl: mp 5556; was evaporated in a vacuum rotary evaporator (Rinco, nmr (CDCl TMS) 81 1.83 (s, 1, hydrogen bonded 25), and the residue was recrystallized from 200 ml of 5S 2OH), 6.90 (s, l, 4OH), 6.33 and 6.30 (2 d, 2, J ether and pentane to give 70.4 g, 0.222 mol (68 per i 2 Hz, aromatic CH), 5.72, 4.92 and 4.88 (3 m, 3,

cent), of white crystalline XXVIl: mp 9l93; .nmr CH=CH 3.82 (s, 3, CH 2.82 (t, 2, J 7 Hz, (CDCl TMS) 58.10 (s, 1,4-OH), 5.72, 4.92 and 4.88 ArCH 2.08 (br m, 2, CH CH=CH and 1.64 ppm (3 m, 3, CH=CH 3.77 (s, 3, CH 3.35 (d, 1, J 10 (br m, 2, CH CH CH Anal. Calcd. for C H C, Hz, HCCOO), 2.72 (dd, 1,1,, 20.4 Hz, J 11.0 66.2; H, 6.8. Found: C, 66.1; H, 6.7. Hz, OCCH CH), 2.43 (dd, 1,1,1 20.4 Hz, J, =86 In Example 28. the dehydrobromination of com- Hz, OCCH CH), 2.06 (br m, 2, CH CH=CH and pound XXVll can be effected at temperatures in the 1.45 ppm (br m, 5, CH(CH- CH Anal. Calcd. for range 60C12()C but a temperature near C is pre- C H O Br: C, 49.2; H, 5.4; Br, 25.2. Found: C, 48.9; fcrred. At a temperature of 65C the rate of dehydro- H, 5.7; Br, 25.2. M hromination is reasonably fast.

In Example 27, the temperature at which the reaction The dehydrobromination step could be carried out in of bromine with Compound XXVI is allowed to occur an alcohol other than methanol, for example ethanol or is kept at 0C in order to minimize the reaction of brobutanol.

EXAMPLE 29 Example 29 delineates the conditions for the product on of ethyl 6-(4-pentenyl)-B-resorcylate by the fo1- lowing general reactions wherein X 4:

Ethyl 6-(4-pentenyl)-B-resorcylate XXIX. A solution containing 19.33 g, 0.0610 mol, of XXVII, and sodium cthoxide (prepared from 9.00 g, 0.391 g-atom, of sodium and in the 250 ml of ethanol) was held at reflux under nitrogen for 6 hr, and then it was evaporated under vacuum until its volume was about 100 ml. It was diluted with water to 300 ml, and acidified with sulfuric acid (6N) while it was held at The resulting mixture was extracted with ether (3 X 150 ml). The extract was was stirred on a steam bath for 6 hr. 1.0 1 of water was added to it while it was stirred, and then it was held overnight at -l. The product that had crystallized was collected on a filter, and it was recrystallized from a mixture of ethyl ether and ligroin (bp 60-68) to give 45.5 g, 0.106 mol (84 percent), of XXX: mp 49-51": nmr CDCI TMS) 87.32 (m, 10, C6H5), 6.44 (s, 2, aromatic CH), 5.72, 4.92 and 4.88 (3 m, 3, CHCH 4.98 and 4.96 (2 d, 4, C H CH 4.28 (q, 2, J 7 Hz,

then washed with water (4 X 100 ml), decolorized with -z). (t. J 7 Hz, ArCH 2.00 (m, 2,

ride) gave 9.15 g, 0.0366 mol (60 percent), of XXIX: 39

nmr (CD g. TMS) 511.95 (s, l, 2--OH), 7.42 (s, l, 4-OH), 6.33 and 6.30 (2 d, 2, J 2 Hz, aromatic CH), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH 4.40 (q, 2, .1

7 Hz, COOCHZ), 2.85 (t, 2, J 7 Hz, ArCH 2.03 (m, 2, CH CH=CH. 1.64 (br m, 2, CH- CH CH and CH CH=CH), 1.64 (br m, 2, CH CI-I CH and 1.23 ppm (t, 3, .I 7 Hz, CH Anal. Calcd. for C ,,H O C, 78.2: H, 7.0. Found: C, 78.0: H, 6.9.

EXAMPLE 3 1 In Example 31, ethyl 2,4-bis( benzyl0xy)-6-(5- hydroxypentenyl)-benzoate is formed by the following general reactions wherein X 4:

NaOAc 1 CH XXX XXXI Ethyl 2,4-bis( benzyloxy )-6-( S-hydroxypentyl benzoate, XXXI. A solution of 8.6 g (0.0197 mol) of 1,40 ppm (t, 3, .I 7 Hz, CH Except for the ex- XXX in 50 m1 of tetrahydrofuran was stirred at 0C pected differences, this nmr spectrum is the same as that of XXVIII above.

EXAMPLE 30 In Example 30, ethyl 6-(4-pentenyl)-,B-resorcylate dibenzyl ether is prepared by the following general reaction wherein X 4:

under nitrogen while 10 m1 of a 0.93 M-diborane (0.0093 mol) solution in the same solvent was dropped in over a period of 30 minutes. Stirring was continued for 5 hours at 25C. The product was then cooled to 0C and the following sequence of reagents added 35 36 c. Addition of 5 ml of 30% hydrogen peroxide. The ative intensity) no parent ion, 713 (M-9l, 3), 712 reaction mixture was then held for an additional hour (3.3), 623 (2.2), 403 (3), 384 (3), 313 (3), 295 (3), at C. 181 (5), 180 (5 91 (100), 65 (6). Anal. Calcd. for The reaction mixture was stirred while 100 ml of C H O C, 7759; H, 6 51 Found; C, 77.55; H, 6,60. th r was add d to llC I -P C miXture WklS P 5 Substance XXXll was also almost insoluble in most or rated, an he aqU p r 21 eXtraCICd further h ganic solvents, and initial attempts at its hydrogenolysis ether (3 X 100 ml). The extract was dried (MgSO and ga only artial rea tion,

then ev porated IO giv 7. g f a y llow l- [t5 nmr The process of the present invention as illustrated by pec m Showed that it was p m the foregoing examples has protected the hydroxyl nantly XXXII 67-25 1; 2), 634 2, 10 groups of the resorcylic acid moiety by forming benzyl AFCH), u s 2-) (q, J ethers in compounds VI, VII, VIII, VIII A, XVIII, XIX, H3 2 3.70 C 2 -53 (m. 2. M xx, xx A, xxx, XXXl, and XXXII. It will be obvious z -l 2-0419 with P at ("L 2( 2' to anyone skilled in the art that other protecting groups 2 and pp (L 3, J (17 HZ, could be used in place of the benzyl group, for exam- 3 2 I5 ple, methyl, ethyl, butyl, cyclopentyl, cyclohexyl and The reaction of the olefinic compound XXX with dih lik r n Water. yd g PeTOXide and Sodium acetate It will naturally occur to a skilled organic chemist solution in Example 31 is carried out in the temperathat the large ring (so-called Bring) of the zearalane II ture range to This temperature range can be compounds can be extensively modified by the choice extended to 0C to C, if it is desired to do so. At 20 temperatures below 0C the reaction rates are low, and above 50C undesirable side reactions occur.

of the aldehyde used as a starting material in the sequence of reactions shown in Chart I, for example.

Applicants consider all such obvious modifications to EXAMPLE 32 be the full equivalent of the embodiments specifically described herein and to fall within the scope of their m- Example 32 glves conditions for the preparation of 25 venfion the dimeric dilactone from 2,4-bis( benzyloxy)-6-(5 hydroxypentyl)-benzoic acid by the following general We claim: reaction wherein X 4: l. A compound of the formula 0CH2C4;H.1 O CH2CHH5 fn s O O CH;

moved. Slow distillation (2 ml/hr) was continued for 36 hr. The mixture was allowed to cool to 25, and 100 ml of water was added to it. Then 3 N-hydrochloric acid was added until its aqueous phase was acidic. The toluene layer was separated, the aqueous one was extracted with ether (4 X 100 ml), and the combined solution was dried (MgSO Dry column chromatography gave 2.8 g (0.0035 mol, 158) of crude product that was recrystallized from excess methylene chloride (150 ml per gram of XXXII) to give XXXII: mp 2032()4C; nmr (CDCL, very dilute solution. TMS) 57.33 (s, 10, C,;H -,CH 6.42 (s. The compound of claim 6 where X is 9.

2, ArCH 5.00 (s, 4, C ;H -,CH 4.25 (m, 2, CH- The compound of claim 6 where X is 10. O), 2.52 (m, 2, ArCH and 2.10.9 ppm (m, 10. A method of preparing a compound of the for- CH ,(CH- ,);,CH- mass spectrum cV) m/c (rclmula hydroxypentyl)-benzoic acid XXXII. A reaction mix C CH turc containing 6.72 g (0.0155 mol) of XXXI, sodium ethoxide solution made from 0.63 g (0.027 g-atom) of O OR sodium and 50 ml of anhydrous ethanol, and 700 ml of 50 toluene (dried by treatment with sodium) was distilled R0 until all of the ethanol-toluene azeotrope had been rewherein R is hydrogen or benzyl and X is an integer having the value 1 to 13 inclusive.

. The compound of claim 1 wherein R is hydrogen. The compound of claim 2 where X is 4.

The compound of claim 2 where X is 9.

The compound of claim 2 where X is 10.

The compound of claim 1 wherein R is benzyl. The compound of claim 6 where X is 4.

comprising reacting a compound of the formula OCH. ,-CH;,

with sodium ethoxide in an anhydrous ethanol-toluene menstruum in an atmosphere substantially devoid of oxygen while distilling the ethanol-toluene azeotrope to remove all of the ethanol and part of the toluene at a temperature in the range of C. to l20C., wherein R is methyl or ethyl and wherein X is an integer having the value 1 to 13 inclusive.

1]. The method of preparing the compound where X is 4 according to the method of claim 10.

12. The method of preparing the compound where X is 9 according to the method of claim 10.

13. The method of preparing the compound where X is 10 according to the method of claim 10.

14. A method for preparing the dimcric dilactone from 6-( 1 l-hydroxyundecyl),B-resorcylic acid comprising hydrogenating the dimeric dilactone from 2,4 bis(benzyloxy)-6-( l l-hydroxyundecyl)-benzoic acid in a menstruum of ethanol and ethyl acetate containing a small amount of triethylamine under a hydrogen pressure of substantially 1 atmosphere and at a temperature of about 25C using palladium on charcoal as a catalyst. 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 wherein R is hydrogen.
 3. The compound of claim 2 where X is
 4. 4. The compound of claim 2 where X is
 9. 5. The compound of claim 2 where X is
 10. 6. The compound of claim 1 wherein R is benzyl.
 7. The compound of claim 6 where X is
 4. 8. The compound of claim 6 where X is
 9. 9. The compound of claim 6 where X is
 10. 10. A method of preparing a compound of the formula
 11. The method of preparing the compound where X is 4 according to the method of claim
 10. 12. The method of preparing the compound where X is 9 according to the method of claim
 10. 13. The method of preparing the compound where X is 10 according to the method of claim
 10. 14. A method for preparing the dimeric dilactone from 6-(11-hydroxyundecyl)- Beta -resorcylic acid comprising hydrogenating the dimeric dilactone from 2,4-bis(benzyloxy)-6-(11-hydroxyundecyl)-benzoic acid in a menstruum of ethanol and ethyl acetate containing a small amount of triethylamine under a hydrogen pressure of substantially 1 atmosphere and at a temperature of about 25*C using palladium on charcoal as a catalyst. 